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Arch Pharm (Weinheim). 2019 May;352(5):e1800315. doi: 10.1002/ardp.201800315. Epub 2019 Apr 26.

Novel calcitriol analogue with an oxolane group: In vitro, in vivo, and in silico studies.

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Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, Bahía Blanca, Argentina.
Departamento de Química Orgánica, Facultad de Química, Universidad de Vigo, Vigo, España.
Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA)-CONICET, Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.


The active form of vitamin D3 , calcitriol, is a potent antiproliferative compound. However, when effective antitumor doses of calcitriol are used, hypercalcemic effects are observed, thus blocking its therapeutic application. To overcome this problem, structural analogues have been designed with the aim of retaining or even increasing the antitumor effects while decreasing its calcemic activity. This report aims at gaining insights into the structure-activity relationships of the novel oxolane-containing analogue, AM-27, recently synthesized. We herein demonstrate that this compound has antiproliferative and antimigratory effects in squamous cell carcinoma, glioblastoma, and breast cancer cell lines. Analyses of the mechanisms underlying the AM-27 effects on cell viability revealed induction of apoptosis by the analogue. Importantly, nonmalignant cell lines were little or not affected by the compound. In addition, the analogue did not produce hypercalcemia in mice. Also, in silico studies involving docking and molecular dynamics techniques showed that AM-27 is able to bind to the human vitamin D receptor with a higher affinity than the natural ligand calcitriol, a feature that is mostly derived from an electrostatic interaction pattern. Altogether, the proapoptotic effect observed in cancer cells, the lack of calcemic activity in mice, and the differential effects in normal cells suggest the potential of AM-27 as a therapeutic compound for cancer treatment.


analogue; calcitriol; cancer; oxolane; vitamin D receptor


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